Paraspinal muscle gene expression across different aetiologies in individuals undergoing surgery for lumbar spine pathology.

PURPOSE: The purpose of this study was to understand potential baseline transcriptional expression differences in paraspinal skeletal muscle from patients with different underlying lumbar pathologies by comparing multifidus gene expression profiles across individuals with either disc herniation, facet arthropathy, or degenerative spondylolisthesis. METHODS: Multifidus biopsies were obtained from patients (n = 44) undergoing lumbar surgery for either disc herniation, facet arthropathy, or degenerative spondylolisthesis. Diagnostic categories were based on magnetic resonance images, radiology reports, and intraoperative reports. Gene expression for 42 genes was analysed using qPCR. A one-way analysis of variance was performed for each gene to determine differences in expression across diagnostic groups. Corrections for multiple comparisons across genes (Benjamini-Hochberg) and for between-group post hoc comparisons (Sidak) were applied. RESULTS: Adipogenic gene (ADIPOQ) expression was higher in the disc herniation group when compared to the facet arthropathy group (p = 0.032). Adipogenic gene (PPARD) expression was higher in the degenerative spondylolisthesis group when compared to the disc herniation group (p = 0.013), although absolute gene expression levels for all groups was low. Fibrogenic gene (COL3A1) had significantly higher expression in the disc herniation group and facet arthropathy group when compared to the degenerative spondylolisthesis group (p < 0.001 and p = 0.038, respectively). When adjusted for multiple comparisons, only COL3A1 remained significant (p = 0.012). CONCLUSION: Individuals with disc herniation and facet arthropathy demonstrate higher COL3A1 gene expression compared to those with degenerative spondylolisthesis. Future research is required to further understand the biological relevance of these transcriptional differences.

Characterization of degenerative human facet joints and facet joint capsular tissues.

OBJECTIVE: Lumbar facet joint degeneration (FJD) may be an important cause of low back pain (LBP) and sciatica. The goal of this study was to characterize cellular alterations of inflammatory factor expression and neovascularization in human degenerative facet joint capsular (FJC) tissue. These alterations in FJC tissues in pain stimulation were also assessed. DESIGN: FJs were obtained from consented patients undergoing spinal reconstruction surgery and cadaveric donors with no history of back pain. Histological analyses of the FJs were performed. Cytokine antibody array and quantitative real-time polymerase chain reaction (qPCR) were used to determine the production of inflammatory cytokines, and western blotting analyses (WB) were used to assay for cartilage-degrading enzymes and pain mediators. Ex vivo rat dorsal root ganglion (DRG) co-culture with human FJC tissues was also performed. RESULTS: Increased neovascularization, inflammatory cell infiltration, and pain-related axonal-promoting factors were observed in degenerative FJCs surgically obtained from symptomatic subjects. Increased VEGF, (NGF/TrkA), and sensory neuronal distribution were also detected in degenerative FJC tissues from subjects with LBP. qPCR and WB results demonstrated highly upregulated inflammatory cytokines, pain mediators, and cartilage-degrading enzymes in degenerative FJCs. Results from ex vivo co-culture of the DRG and FJC tissue demonstrated that degenerative FJCs increased the expression of inflammatory pain molecules in the sensory neurons. CONCLUSION: Degenerative FJCs possess greatly increased inflammatory and angiogenic features, suggesting that these factors play an important role in the progression of FJD and serve as a link between joint degeneration and neurological stimulation of afferent pain fibers.

Association between estrogen receptor gene polymorphism and back pain intensity in female patients with degenerative lumbar spondylolisthesis.

STUDY DESIGN: Prospective study. OBJECTIVE: To examine the possible association of estrogen receptor α (ERα) polymorphisms and pain intensity in symptomatic female degenerative spondylolisthesis (DS) patients. SUMMARY OF BACKGROUND DATA: DS has been associated with a significant sex effect. Thus, several studies about the association between the ER gene and osteoarthritis have been reported. However, whether estrogen is associated with pain sensitivity is inconsistent in the existing literatures from both human and animal studies. METHODS: The PvuII and XbaI polymorphisms, bone mineral density at the lumbar spine (LSBMD) and at the femoral neck (FNBMD), pain intensity at the leg and lower back, and radiologic and anthropometric findings were analyzed in 192 patients with DS. RESULTS: There was a significant association between XbaI polymorphism and the visual analog scale score of back pain. The back pain visual analog scale in patients with a GG genotype was significantly higher than in patients with the AG (P<0.05) or the AA (P<0.05) genotypes. In addition, the presence of the CG haplotype was found to be associated with back pain intensity in the haplotype analysis of the PvuII and the XbaI polymorphisms of ERα. CONCLUSIONS: These results suggest that the ERα gene polymorphism using XbaI restriction enzyme influences the perception of back pain in patients with DS.

Type IX collagen neo-deposition in degenerative discs of surgical patients whether genotyped plus or minus for COL9 risk alleles.

STUDY DESIGN: Immunohistochemical analysis of type IX collagen in disc tissue from spinal fusion patients. OBJECTIVE: To determine if collagen IX can be detected in adult disc tissue removed at spinal fusion surgery from patients either with or without degeneration-associated tryptophan single nucleotide polymorphisms (SNPs) and whether the distribution is associated either with severity of degeneration or incidence of a collagen IX SNP genotype. SUMMARY OF BACKGROUND DATA: Genetic factors are strongly associated with risk of development and/or progression of disc degeneration. Two SNPs that introduce tryptophan polymorphisms in COL9A2 and COL9A3 are independently linked to an increased risk of lumbar disc disease. Although tryptophan variants are associated with accelerated degeneration, it is not known if collagen IX can be detected in adult disc tissue. METHODS: We selected age-matched disc samples from five clinical groups: fracture with Trp(-) (six cases), herniation (six cases), degeneration (five cases), spondylolisthesis with Trp(-) (eight cases), and spondylolisthesis/herniation/fracture with Trp(+) (six cases of Trp3 allele and one case of Trp2 allele). Using hematoxylin and eosin staining and immunohistochemical staining (collagens IX and IIA), 78 sections from 32 patients were analyzed. Selected disc tissues were assayed biochemically for collagen IX. RESULTS: Focal deposition of collagen IX was observed in regions of adult human disc tissue from spines showing degenerative changes in patients whether or not they were positive for a tryptophan SNP. However, in nondegenerative control disc tissue from fracture cases, little or no collagen IX was detected. The latter finding was confirmed by direct biochemical analyses for collagen IX in pooled samples of normal adult human annulus fibrosus or nucleus pulposus. CONCLUSION: During growth and maturation of the disc, collagen IX is presumably removed completely during matrix remodeling so that the protein is absent from normal adult annulus and nucleus but can reappear at sites of degeneration presumably as part of a repair response to mechanical injury.

Spondylolisthesis in twins: multifactorial etiology: a case report and review of the literature.

STUDY DESIGN: Report of a high dysplastic developmental spondylolisthesis in two identical twins of two unrelated families. OBJECTIVE: To investigate the multifactorial etiology of developmental spondylolisthesis. SUMMARY OF BACKGROUND DATA: Multiple studies have suggested an association between a high pelvic incidence and the presence of isthmic spondylolisthesis. Other studies suggest a genetic background for spondylolysis and a pattern of inheritance of susceptibility to spondylolysis and spondylolisthesis. Heterozygous cartilage-derived morphogenetic protein-1 (CDMP-1) mutation has previously been associated with spondylolysis and severe spondylolisthesis. METHODS: Two identical female twins presented with a developmental spondylolisthesis. Pelvic parameters, lumbar lordosis and grade of spondylolisthesis were calculated on a lateral standing spine radiograph. MRI is performed to confirm a high dysplastic developmental spondylolisthesis. Blood sample of these four individuals were analyzed for the presence of a CDMP-1 mutation, a cartilage-specific member of the TGF-b superfamily of secreted signaling molecules that plays a key role in chondrogenesis, growth, and patterning of the developing vertebrate skeleton. RESULTS: PI, SS, PT, LL, and SI are significantly greater in all of these patients in comparison with the general population. Spinal MRI confirms a high dysplastic developmental spondylolisthesis in both twins. Mutation analysis of the two coding exons of CDMP-1 did not reveal any mutation in all four individuals. CONCLUSION: To our knowledge, this is the first report of a high dysplastic developmental spondylolisthesis in identical twins. The presence of a high dysplastic developmental spondylolisthesis in two identical twins shows the convergence in etiology of different factors such as genetics, maturation, critical age, female sex, high pelvic incidence. Although we cannot confirm that CDMP-1 mutation plays a key role in the etiology of spondylolysis/spondylolisthesis, neither can we rule out that CDMP-1 problems may be an etiology for at least a subpopulation of patients. However, the presence of a developmental spondylolisthesis in two sets of identical twins still suggests a genetic susceptibility to spondylolysis and spondylolisthesis.

Expression of estrogen receptor of the facet joints in degenerative spondylolisthesis.

STUDY DESIGN: Immunohistochemical study was done by harvesting articular cartilage of the facet joints during the decompressive surgery for spinal stenosis. OBJECTIVES: To observe the expression of estrogen receptor on the articular cartilage of the facet joints in degenerative spondylolisthesis (DS) SUMMARY OF BACKGROUND DATA: Few attempts have been made to evaluate the effect of sex-hormone, although DS is more common in females than in males. METHODS: After harvesting the articular cartilage of the facet joints in 17 DS and in 15 spinal stenosis (SS) patients, the expression of estrogen receptor and the severity of facet arthritis were observed by H-E and immunohistochemical staining, respectively. Measurements of both staining were made by using a semiquantitative analysis. RESULTS: The significantly increased expression of estrogen receptor correlated with the severity of facet arthritis (r = 0.78, P < 0.05). There was a significantly increased expression of estrogen receptor of the facet joint in DS compared with SS (P < 0.01). The histologic-histochemical grading of cartilage lesion in DS was 12.4 (SEM, 0.6), which was significantly higher than in SS (P < 0.05). CONCLUSIONS: These findings suggest that the higher expression of estrogen receptor might aggravate degenerative change of the facet articular cartilage and might also be considered one of the causative factors for DS in postmenopausal women.

The association of lumbar spondylolisthesis with collagen IX tryptophan alleles.

Two collagen type IX gene polymorphisms that introduce a tryptophan residue into the protein's triple-helical domain have been linked to an increased risk of lumbar disc disease. To determine whether a particular subset of symptomatic lumbar disease is specifically associated with these polymorphisms, we performed a prospective case-control study of 107 patients who underwent surgery of the lumbar spine. Patients were assigned to one of five clinical categories (fracture, disc degeneration, disc herniation, spinal stenosis without spondylolisthesis and spinal stenosis with spondylolisthesis) based on history, imaging results, and findings during surgery. Of the 11 tryptophan-positive patients, eight had spinal stenosis with spondylolisthesis and three had disc herniation. The presence of the tryptophan allele was significantly associated with African-American or Asian designation for race (odds ratio 4.61, 95% CI 0.63 to 25.35) and with the diagnosis of spinal stenosis with spondylolisthesis (odds ratio 6.81, 95% CI 1.47 to 41.95). Our findings indicate that tryptophan polymorphisms predispose carriers to the development of symptomatic spinal stenosis associated with spondylolisthesis which requires surgery.

Familial spondylolisthesis of the axis vertebra.

This report describes a nine-year-old girl with a spondylolisthesis of the C2 vertebra allowing 14 mm of slip. Her father had very similar vertebral anomalies.

Family study of spondylolysis and spondylolisthesis.

Seventy index patients and 222 first-degree relatives with spondylolysis or spondylolisthesis have been studied by means of interview and clinical and radiological examinations. The index patients had an average age of 18 years, and included 43 females and 27 males. Following Wiltse's classification, 18 patients had dysplastic lesions and 52 had isthmic defects. The first-degree relatives included 99 parents and 125 siblings and children of the index patients. Both isthmic and dysplastic defects occurred in most families, regardless of the classification of the index patient. Isthmic defects were consistently more frequent than dysplastic defects. Spina bifida occulta occurred at the lumbosacral area in 61% of the index patients; in the first-degree relatives, spina bifida occulta was most common among the siblings and children of index patients, and occurred more often in relatives of index patients with dysplastic lesions than in those with isthmic lesions.

Inheritance and spondylolisthesis: a radiographic family survey.

A radiographic suvey has been carried out of 147 first-degree relatives of forty-seven patients treated in Edinburgh for spondylolisthesis of the fifth lumbar vertebra; twelve patients had the dysplastic (congenital) type and thirty-five an isthmic defect. The survey identified 19 per cent of relatives with spondylolysis, and index patients with each type of spondylolisthesis had relatives with the opposite type. Index patients with the dysplastic form had a higher proportion of affected relatives (33 per cent) than had those with the isthmic type (15 per cent), but both figures were significantly in excess of the estimated frequency for the general population of under 1 per cent and 5 per cent respectively. Spina bifida occulta at the fifth lumbar or first sacral level or both, and lumbosacral segmental defects were commoner amongst all individuals with spondylolysis than amongst unaffected relatives (dysplastic form 94 per cent, isthmic type 32 per cent, unaffected relatives 7 per cent). However, there was no single instance of a neural tube defect (anencephaly, spina bifida with or without meningocele, other generalised vertebral anomalies or spinal dysraphism) amongst 826 first-, second- or third-degree relatives. It is concluded that the developmental defects of the vertebrae associated with spondylolysis are not aetiologically related to the neural tube defects. The one in three risk of spondylolysis to near relatives of patients with the dysplastic form of spondylolisthesis is emphasised in order that the deformity in their sibs and children can be recognised at any early age.

Etiology of spondylolisthesis.

The etiology of spondylolisthesis is multiple according to the type of the vertebral slipping. In fact all the following basic pathological processes may be involved: congenital malformation of the upper sacrum in the dysplastic spondylolisthesis; growth dysplasia of the vertebral arch in the "isthmic spondylolisthesis" where an hereditary background and mechanical stresses play a determining role; degenerative conditions of the intervertebral joints in "degenerative spondylolisthesis" of Newman or the "pseudospondylolisthesis" of Junghanns; infections and benign or malignant tumors destroying the articular bolt maintaining the vertebral line; traumatic lesions such as multiple fractures of the bony hook or much more rarely an isolated bilateral fracture of the pars interarticularis.

Selection of broiler chickens for a high and low incidence of tibial dyschondroplasia with observations on spondylolisthesis and twisted legs (perosis).

Radiography was used to select normal birds and affected with tibial dyschondroplasia from a commercial stock of broiler chickens. Birds were selected for three generations and mated like to like in an attempt to establish low and high incidence strains. Incidence of tibial dyschondroplasia in the low incidence strain was reduced to negligible levels while it was increased in the high incidence strain. Incidence of the defect in the high incidence strain could be influenced by diet. Observations during the selection program on the incidence of spondylolisthesis and twisted legs in birds younger than eight weeks of age indicated that these other skeletal defects were unrelated to tibial dyschondroplasia.

Fatigue fracture: the basic lesion is inthmic spondylolisthesis.

The defect in the pars interarticularis in spondylolysis and spondylolisthesis is most often the result of repeated trauma, stress, and factors other than acute fracture. These fatigue fractures develop early in life, may have a strong hereditary basis, and most often represent incidental roentgenographic findings. Attention should be given to the youngster or adolescent with low-back pain and paraspinal muscle spasm. If these patients are followed closely, the incidence of pars interarticularis defect is higher than appreciated. The lesion in some of these individuals may progress to significant vertebral slipping. If the developing defect is recognized early, treatment can be quite satisfactory.